Impacts of environmental tobacco smoke on the onset and progression of multiple sclerosis: a systematic review

Background  Unlike cigarette smoking, environmental tobacco smoke (ETS) has not been as well described as an environmental risk for Multiple sclerosis (MS) nor as a risk factor for disease progression. Objective  We systematically reviewed the association between ETS and the risk of onset and/or progression of MS. Methods  We systematically screened MedLine/PubMed, Science Direct, LILACs, and SciELO searching for publications between January 1st, 2010, and July 5, 2021, with the following keywords: “multiple sclerosis and smoking”; “multiple sclerosis and passive smoking”; “multiple sclerosis and secondhand smoking”. Results  Fifteen articles were included in this review, which consisted of systematic reviews with meta-analysis (N = 2), systematic reviews (N = 2), and observational studies (N = 11). Both meta-analyses reported an impact of ETS on MS onset among secondhand smokers. One of the systematic reviews selected two observational studies showing the association between ETS and MS development, and one study that did not find a significant association between ETS and the risk of MS development. The other systematic review identified selected eight articles showing a relationship between ETS and MS. Seven observational studies reported higher odds of MS onset when associated with ETS. Four observational studies did not show a relationship between ETS and MS onset or progression. Conclusion  Most articles showed a positive association between ETS exposure and the risk of developing MS. On the other hand, an association between ETS and a higher risk for MS progression could not be established.


INTRODUCTION
Multiple sclerosis (MS) is a chronic inflammatory demyelinating autoimmune disorder of the central nervous system (CNS). 1 It is the most common demyelinating disease in high-income countries, with a prevalence of approximately 140/100,000 inhabitants in North America and 108/100,000 in Europe. 2 The etiology of MS remains unclear, but environmental and lifestyle components, accompanied by genetic susceptibility, have been associated with an increased risk of MS. 1 Tobacco smoking has been consistently reported as an MS environmental risk, increasing the propensity of developing such a disorder.Moreover, smoking is additionally mentioned as a risk factor for a more aggressive disease progression.In a case-control study, smoking was associated with a 50% increase in risk for MS onset (odds ratio, OR 1.5, 95% confidence interval, CI 1.0-2.1). 3 Furthermore, a cross-sectional study showed that smoking after MS diagnosis is associated with a reduced time for the development of secondary progressive MS. 4 The mechanism underlying the relationship between smoking and MS is not entirely understood.In a study published in 2016, Okinger and colleagues showed that smoking increases the number of alveolar macrophages, in addition to altering the distribution of alveolar macrophages and lymphocytes in the bronchoalveolar lavage fluid. 5With a proinflammatory environment, foreign antigens that are present in smoke, together with sequestered antigens, which are generated by mucosal cells injury, and neoantigens, which are promoted by reactive oxygen species, may result in a crossreaction with self-antigens, inducing autoimmunity. 6oreover, there seems to be an interaction between active smoking and human leukocyte antigen (HLA) complex genes associated with higher MS risk.A case-control study demonstrated the impact of HLA-DRB1 Ã 15 and HLA-A Ã 02 on MS predisposition.When smoking was linked to the carriage of HLA-DRB1 Ã 15 and absence of HLA-A Ã 02, the OR was 13.5 (95% CI 8. 1-22.6).On the other hand, smokers without both risk genotypes presented an OR of 1.4 (95% CI 0.9-2.1). 7nlike cigarette smoking, environmental tobacco smoke (ETS)which is formed from the burning of cigarettes and other tobacco products and from smoke exhaled by the smoker has not been as well described as an environmental risk for MS nor as a risk factor for disease progression. 8It is important to note that although the overall exposure to ETS among nonsmokers in the US has declined between the years 1988 and 2014, its prevalence has not decreased significantly in recent years.In addition, 25% of nonsmokers, including 14 million Conclusion Most articles showed a positive association between ETS exposure and the risk of developing MS.On the other hand, an association between ETS and a higher risk for MS progression could not be established.

Environmental tobacco smoke and multiple sclerosis
Schlindwein et al.
children, were exposed to ETS between 2013 and 2014. 9Thus, it would be of great importance to establish whether ETS impacts the onset or progression of MS.Therefore, we conducted a systematic review to analyze the association between ETS and the risk of onset and/or progression of MS.

METHODS
This systematic review was conducted according to the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement (https://pubmed.ncbi.nlm.nih.gov/19621072/).There was no previous protocol registered.2.1 Literature search.
The authors systematically screened MedLine/PubMed, Science Direct, LILACs, and SciELO from July 5, 2021, to August 13, 2021, with the following keywords: "multiple sclerosis and smoking"; "multiple sclerosis and passive smoking"; "multiple sclerosis and secondhand smoking".An 11-year filter was applied (from 2010 to 2021).

Eligibility criteria
The eligibility criteria encompassed studies that: • were published in English, Spanish or Portuguese; • described the association between passive/secondhand/ environmental tobacco smoking and MS; • were published between January 1st , 2010, and July 5, 2021; and • were either prospective or retrospective clinical trials, case reports, systematic reviews, or meta-analyses.
The present paper did not include studies that: • presented other study designs, such as non-systematic reviews; • were not indexed in the screened platforms; and • did not describe the association between passive/secondhand smoke and MS.Additionally, duplicate articles were only counted once.

Risk of bias
Two independent reviewers (CSS and VC) conducted the primary literature research using the previously described search terms.At first, titles and abstracts were screened based on the eligibility criteria.The full texts of all the screened abstracts were evaluated by a third reviewer (MAMS).In case of doubt, the most experienced author (MVMG) re-evaluated the studies.Two independent reviewers (BSC and MHMC) assessed the risk of bias in each systematic review and meta-analysis according to the AMSTAR 2 guidelines, 10 whereas observational studies were analyzed using The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Non-randomized Studies in Metaanalyses. 11No study was excluded based on the risk of bias.

Data extraction and synthesis
Using the keywords, 626 articles were identified in the MedLine/PubMed platform.In ScienceDirect, 15,696 articles were identified, and 12 of those were duplicated.Four articles were identified in LILACs.No articles were found on the SciELO platform.Thus, 16,314 articles were screened for title and abstract and 16,225 were excluded because they did not fit in the inclusion criteria, especially due to study design.Subsequently, 89 full texts were reviewed (83 from MedLine/PubMed and 5 from Science Direct) and 74 were excluded after full-text reading, mainly for not having data on ETS and MS.Finally, 15 studies were included in this review.►Figure 1 illustrates the flow chart, according to the PRISMA statement.

RESULTS
The 15 studies included in this review consisted of systematic reviews with meta-analyses (N ¼ 2), systematic reviews (N ¼ 2) and observational studies (N ¼ 11).Among the 11 observational studies, four were exclusively about ETS, six were non-exclusively about ETS, and the last one was about waterpipe smoking.►Table 1 summarizes all studies included with their populations, main findings, and limitations.Both meta-analyses included in the present study reported an impact of ETS on MS onset among secondhand smokers.One of them, published in 2017 by Poorolajal and colleagues, included three articles with an overall OR of 1.12 (95% CI: 0.87-1.36)and heterogeneity of I2 ¼ 66%. 12The other, published in 2016 by Zhang and colleagues, included 3 studiesof which 2 were also selected in the study by Poorolajal et al. and showed an OR of 1.24 (95% CI 1.03-1.49)and a heterogeneity of I2 ¼ 67%. 13urthermore, a systematic review from Canada selected 2 observational studies showing the association between ETS and MS development. 14The first one was a French study  Meta-analysis, Iran, 2017.

À
The study indicated that both former and current smokers are predisposed to develop Multiple Sclerosis (MS).The risk increases proportionally to the number of cigarettes smoked per day.The meta-analysis selected 3 studies that show the association between MS and environmental tobacco smoke (ETS).Among second-hand smokers, the estimated Odds Ratio (OR) of MS was 1.12, when compared with nonsmokers.(I) Does not identify which studies had the association between MS and ETS.
(II) Data regarding environmental tobacco smokers was not detailly provided.
(III) Does not detailly described selected studies.(IV) Limited number of studies in some subgroups.(V) The majority of articles selected were low-quality studies.

À
The study shows that smoking is an environmental risk to MS.The meta-analysis also identified three studies containing four study populations that show the association between ETS and MS, reporting an overall OR of 1.24.The study did not use a technique for assessing the risk of bias in the individual studies included.
McKay et al.  2007) reported an association between parental smoking and the early onset of MS in their children (OR 2.12), with a higher risk in older children, when compared to younger ones.Gardener et al. (2009) showed that children whose parents used to smoke at home had an increased risk of MS; however, when restricted to the cases that were non-smokers as adults, it was not statistically significant (OR 1.2, CI 0.90-1.5).The vast literature present in the study limited the full discussion of some papers included, for example the strengths and limitations of each study.

Degelman and
Herman.Environmental tobacco smoke and multiple sclerosis Schlindwein et al. showing a relationship between ETS and MS onset (OR of 2.12). 14The other study is a cohort of female nurses from the USA, included in Degelman and Herman's article as well, and it did not show a significant association between ETS and the risk of MS development (OR 1.2, CI 0.90-1.5). 14,15A third study, carried out by Hedström et al., was also included by McKay and colleagues and also selected for the present article, which will be further described. 14,21he other systematic review identified for the present study selected eight articles showing a relationship between ETS and MS. 15 Four of them reported a positive association between ETS and MS development, whereas the other four studies showed no interaction. 15mong the twelve observational studies identified, seven of them reported higher odds of MS onset when associated with ETS.A case-control study from Denmark showed an OR for MS risk of 1.43 among females in the first cohort studied, and an OR for MS risk of 1.593 among males in the second cohort. 16The population included, comprising a total of 2,589 individuals, was divided into never-smokers, with 342 cases and 590 controls, and those who became smokers after the age of 19 years, with 577 cases and 1,080 controls.In men who became active smokers in adulthood, the association between ETS and the disorder showed an OR of 1.593 (95% CI 1.070-2.372).In contrast, among women who had never smoked, ETS was associated with MS risk (OR 1.43, 95% CI 1.02 to 2.01). 16nother study, from Japan, with a cohort comprising 227 individuals, reported that exposure to ETS was associated with greater MS risk, displaying an OR of 1.31 ( 95% CI 1.05-1.63). 17Moreover, a cohort composed of 216 children with acquired demyelinating syndromes (ADS) and 81 children with MS showed that 37% of patients that progressed to MS were exposed to ETS, whereas among patients with monophasic ADS, 29.5% were exposed. 18In Iran, a case-control study, with 547 subjects with MS and 1,057 controls, showed an OR of 1.85 (95% CI 1.48-2.32)for MS development. 19hree studies from Sweden reported higher MS risk.One of them, a cohort with 7,791 individuals, displayed an OR of 1.1 (95% CI 1.0-1.3),][22] Four observational studies did not show a relationship between ETS and MS risk.A cross-sectional study from Colombia, composed of 87 MS cases and 87 controls, all older than 18 years, reported that this association was not statically significant (p ¼ 0.5959). 23A study from Iran, composed of 660 individuals with MS, reported an OR of 0.79 for MS progression risk associated with ETS exposure. 24The impact of ETS on MS progression was also analyzed in a study from Italy, composed of 131 individuals with MS, revealing that no significant relationship was found. 25In a case-control study from the United Kingdom, comprising 3,157 MS cases and 756 controls, individuals that were exposed to ETS at home presented an OR of 0.87 (95% CI 0.71-1.41),whereas exposure at the workplace showed an OR of 0.99 (95% CI 0.71-1.41). 26

Systematic reviews and meta-analyses
3][14][15] However, none of them approached ETS exclusively.Three of them were focused on the effects of smoking and MS risk, including ETS among smoking types. 12,13,15The other one included a variety of factors associated with MS development risk, relapse, and progression. 14mong these papers, the most recent was published in 2017 by Degelman and Herman, who performed a systematic review utilizing the Bradford Hill criteria for causation between smoking and both MS development risk and MS progression risk. 15There were eight articles on ETS and MS risk included in this study.Four of them showed positive results between the association of ETS exposure and the risk of MS; one was exclusively focused on children, one utilized cotinine as a marker of exposure, and the other two articles detected a dose-dependent risk using time of exposure as a measure.The other four studies included, however, failed to show a significant association between ETS and the risk of MS development.Three of them were case-control studies while the other one was a cohort of female nurses.In this systematic review, the authors were unable to perform a metaanalysis due to the heterogeneity among the eight studies.There were discrepancies regarding the definition of ETS, and the characteristics of the populations studied were not comparable.Degelman and Herman additionally commented on mixed results from other two meta-analyses, which were also included in the present paper and are discussed further separately. 12,13,15ne of the meta-analyses cited by Dengelman and Herman was published in 2017 by Poorolajal and colleagues, with a focus on the evaluation of different types of smoking exposure and their influence on MS onset. 12Regarding ETS, this study shows an overall OR of 1.12 (95% CI: 0.87-1.36)and substantial heterogeneity of I2 ¼ 66%.However, these results were briefly shown and were not described in detail in the meta-analyses. 12he other meta-analysis was published in 2016. 13Zhang and colleagues found a significant relationship between ETS and MS (OR of 1.24, 95% CI 1.03-1.49),but also a similar heterogeneity found in the study by Poorolajal and colleagues (I 2 ¼ 67%). 13he fourth systematic review included in the present study, published in 2017, was not focused on ETS and neither on smoking; instead, it encompassed all factors associated with MS onset, relapse, and progression. 14McKay and colleagues included two articles on ETS that were published before 2010, which were not included in the present review due to the established publication year restriction. 14The French study, that evaluated the risk of parental home smoking and MS development, shows a significant relationship between ETS in childhood and early MS onset (OR of 2.12).In addition, this study shows a higher risk in older children -older than 10 years -when compared to younger ones (relative risk, RR of 2.49). 14The other study was the cohort of female nurses included in Degelman and Herman's article as well. 14,15The third study, performed by Hedström et al., was also included by McKay and colleagues and also selected for the present article, which will be further discussed. 14,21ence, ETS was never the main topic of a systematic review.Even in papers published over the same period of timewith similar methodologies -, there is an important disparity in the results displayed.An important factor that may have caused this variety regards the large number of different terms representing ETS found in the databases ("passive smoking"; "secondhand smoking"; "smoking exposure"; "environmental smoking").This can make it more difficult to select all articles of interest.

Observational studies
7][18][19][20][21][22][23][24][25][26] They are either case-control or cohort studies evaluating either ETS and MS development risk or the impact of ETS on MS progression.Four of these articles were designed exclusively to assess the relationship between ETS and MS, whereas the others assessed ETS among other different factors for MS development or progression.
Among the four studies designed exclusively to analyze ETS as an environmental risk factor for developing MS, the oldest one is a case-control study, published in 2011, that included only subjects that had never smoked, evaluating the impact of ETS on the risk of developing MS. 21The authors also analyzed confounding factors such as serum vitamin D levels and Epstein Barr virus status in this population.The results showed that 39% of cases and 34% of controls were exposed to ETS and that the exposure occurred almost exclusively at home.The study found a higher MS risk in subjects exposed to ETS compared to those who had never been exposed.In addition, the article revealed a trend suggesting that longer exposure time resulted in higher risk, showing an OR of 1.8 (95% CI 1.2-2.6)with a 20-year exposure. 21nother study by Hedström and colleagues included in our review provided data on the interaction between the HLA-DRB1 Ã 15 and HLA-A Ã 02 genotypesthe former being associated with an increased risk of MS and the latter having a protective effect for MS. 22As in their previous study, confounding factors, such as vitamin D and Epstein Barr virus status, were analyzed and the selection of subjects was restricted to people who never smoked.Non-smokers who also have never been exposed to ETS presented a higher risk of developing MS when they presented both genetic risks (OR 4.5, 95% CI 3.3-6.1).When individuals with the same genotype were exposed to ETS, the risk of developing MS increased significantly (OR 7.7, 95% CI 5.5-10.8),showing that ETS may be an independent risk factor for MS onset. 22avery and colleagues explored the effects of ETS in a USA cohort composed of children with ADS and children with MS. 18 The study showed that both groups had an association with ETS exposure.In addition, an investigation between the interaction of HLA-DRB1 Ã 15 and ETS was carried out, show-ing that carriage of this genotypewhich was observed in 41.9% of the MS cohortwithout ETS exposure did not increase the risk of developing MS.When both ETS exposure and the genotype were present, the OR for MS increased to 3.71 (95% CI 1.17-11.9).Together, these two factors accounted for a 54% MS risk. 18he most recent study that focused on ETS as a risk factor for developing MS was published in 2021. 16Oturai and colleagues explored the exposure to ETS during adolescence (from 10 to 19 years old) and its relationship with MS.Subjects that were smokers before the age of 19 years were excluded.Interestingly, ETS was not associated with MS in men who had never smoked.However, in men who became active smokers in adulthood, the association between ETS and the disorder showed an OR of 1.593.On the contrary, among women who had never smoked, ETS was associated with MS risk, increasing the odds of developing the disorder by 4.6% for each year of exposure.Also, in women who became active smokers after 19 years of age, ETS during adolescence did not increase the chances of developing MS. 164][25][26] Among these studies, two of themone from Japan and the other from Swedenshowed that ETS was associated with an increased risk for MS. 17,20In the Japanese study, ETS exposure was evaluated in subjects older than 16 years, showing a positive relationship with MS. 17 In the Swedish cohort, individuals who were exposed to ETS for more than 20 years and reported actively smoking more than 10 pack-years had an almost three-times higher risk of developing MS.Interestingly, this cohort also showed a dose-response relationship between years of exposure to ETS and the risk of MS.Individuals who were exposed to ETS for less than 20 years displayed an OR of 1.1 (95% CI 1.0-1.3)for MS, while exposure for more than 20 years showed an OR of 1.4 (CI 95% 1.1-1.8). 20ith regards to studies that found negative results, a Canadian case-control study performed a questionnaire to investigate lifetime cigarette smoking and ETS exposure with MS development. 26Among never-smoker subjects (N ¼ 1,394) there was no association between MS risk and ETS exposure either at home or at the workplace. 26The other is a Colombian study in which subjects were interviewed to assess environmental risk factors for MS.Regarding ETS, subjects were asked if they were exposed between the ages of 19 to 25 years.Neither cigarette nor ETS history had a statistically significant association with an increased risk for MS onset. 23wo additional studies evaluated the impact of ETS on the disease's severity and progression; however, they showed no association. 24,25An Italian cohort completed a questionnaire about lifetime smoking habits.Moreover, the authors of the study considered ETS exposure only over the 12 months prior to the questionnaire.The study did not identify a significant association between either cigarette smoking status or exposure to ETS and the severity of MS. 25 In the other study, an interview regarding environmental risk factors for MS severity was carried out with an Iranian cohort.This study showed that ETS was not related to MS severity. 24he last one, an Iranian case-control study evaluated the risk between waterpipe smoke and MS development. 19This article showed that, besides active waterpipe smoke, ETS was associated with MS risk, displaying an important impact with a dose-dependent increase in risk.Interestingly, in this study, ETS during childhood and adolescence was not statistically significant for increasing the risk of MS.Furthermore, the study shows that subjects exposed to all three modes analyzed (waterpipe smoke, tobacco smoke, and secondhand smoke) had a 4.1 higher odds of having MS compared to subjects that were not exposed. 19s with the systematic reviews and meta-analysis, the majority of observational studies also did not focus on ETS exclusively.In addition, there may be imprecision in the methods of quantifying exposure to ETS.Unlike active smoking, which has some quantitative measures such as pack years, exposure to ETS is usually measured based on questionnaires referring to the subject's exposure history, which makes the information more susceptible to recall bias.

Study limitations
As a limitation of our study, the large number of different terms representing ETS found in the databases may have led to difficulties in selecting all articles of interest; With that in mind, the researchers examined a large number of studies, including all different terms that could represent ETS.
In conclusion, as shown from the studies selected by the present review, the majority of articles displayed a positive association between ETS exposure and the risk of developing MS.In addition, when considering only studies that were exclusively designed to evaluate ETS exposure, the association was found in all of them.Some articles showed that exposure during childhood resulted in a considerably higher risk.Also, the reviewed data about the relationship between ETS and genetic risk factors, such as HLA-DRB1 Ã 15 and HLA-A Ã 02 genotypes, shows a strong impact on the odds of developing the disorder.Moreover, a dose-dependent risk relationship between years of exposure to ETS and MS risk was observed in some cohorts.On the other hand, the association between ETS and a higher risk for MS progression could not be established.
Overall, the present study shows evidence of the impact of ETS on the development of MS and encourages further studies addressing this topic to strengthen the establishment of this association.

Figure 1
Figure 1 Flow chart, according to the PRISMA statement.

Table 1
Compilation of the included primary articles I) Studies included regarding the association between ETS and MS were not described in detail.(II) Quality of study evidence for each outcome was either low or very low.
À Four out of the eight articles analyzed, which cited the correlation between ETS and MS, demonstrated a statistically significant association.Meta-analysis was not performed due to heterogeneity among studies.(Arquivos de Neuro-Psiquiatria Vol.82 No. 3/2024 © 2024.The Author(s).

Table 1 (
Continued) Recall bias may be present, as subjects were asked about their past experience and habits.(II) Authors considered ETS exposure only at home and did not consider the experience in other places, for example while outdoors or workplace.Recall bias may be present, as subjects were asked about their experience and habits.(II) Authors considered ETS exposure only in the workplace or at home and did not consider the experience in other places, for example while outdoors.